5-thiocarbamylimino-4-substituted-delta2-1,3,4-thiadiazoline-2-sulfonamides



S-TI-IIOCARBANIYL-4-=SUBSTITUTED A 1,3,4- THIADIAZOLINE-Z-SULFONAWES Richard William Young, Riverside, and Melinda Jane Muller, Stamford, Conn., assignors to American Cyan- Marnfld Company, New York, N. Y., a corporation of ante No Drawing. Application August 13, 1956 Serial No. 603,842

12 Claims. (Cl. 260306.8)

Unite-1? wherein R is a lower alkyl radical, amonocyclic 'aryl radical or a monocyclic aralkyl radical. Suitable lower alkyl substituents are methyl, ethyl, propyl, isopropyl, butyl, pentyl, amyl, hexyl, etc.; suitable aralkyl substituents are benzyl, phenethyl, phenylpropyl, phenylbutyl, etc.; and suitable aryl substituents are phenyl and substituted phenyl, suitable substituents on the phenyl ring being Cl, Br, I, --NO OCH and lower alkyl radicals containing from 1 to 4 carbon atoms.

The compounds of this invention may be prepared by reacting a suitable isothiocyanate with an appropriate '5-imino-4-substituted-A -1,3,4-thiadiazoline-Z-sulfonamide in the presence of a basic organic solvent such' as pyridine by heating to temperatures of the order of from room temperature to about 150 C. 'Other suitable solvents'for this reaction in addition'to pyridine are dirnethylarnine,

tributylamine, quinoline, lutidine, etc.

Suitableisothiocyanates used in this reaction aregfor example, methylisothiocyanate, ethylisothiocyanate, butyl isothiocyanate, isobutylisothiocyanate, n-valerylisothiocyanate, allylisothiocyanate, phenylisothiocyanate, pchlorophenylisothiocyanate, pacetamidophenylisothiocyanate, m-methoxyphenylisothiocyanate, m-tolylisothiocyanate, Z-naphthylisothiocyanate and benzylisothiocyanate.

The 5-imino-4-substituted-A -1,3,4-thiadiazoline-2-sulfonamides which are used as starting materials for the products of this invention are preferably prepared by the acid hydrolysis of 5-acylimino-4-substituted-A 1,3,4-thiadiazoline-Z-sulfonamides which are more particularly described and claimed in the copending application of Young, Wood and Vaughan, Serial No. 492,297, filed March 4, 1955, now Patent No. 2,783,241, and in the copending application of Young and Muller, Serial No. 560,866, filed January 23, 1956, now Patent No. 2,783,239. Among the suitable 5-imino-4-substituted-A 1,3,4-thiadiazoline-Z-sulfonamides which may be used in carrying out this invention there may be mentioned 5-imino-4-methyl-A -l,3,4-thiadiazoline-2 sulfonamide, 5-imino-4-ethyl-A -1,3,4-thiadiazoline 2 sulfonamide, 5- imino-4-benzyl-A -1,3,4-thiadiazo1ine 2 sulfonamide, 5- imino-4-phenyl-A -1,3,4-thiadiazoline 2 sulfonamide, 5- imino-4-(m-tolyl)-A -1,3,4-thiadiazoline-2-sulfonamide, 5- imino-4- p-chlorophenyl -A 1 ,3 ,4thiadiazoline-Z-sulfonamide, 5-imino-4-(p-acetamidophenyl )-A -1,3,4-thiadiazoline-2-sulfonamide, 5-imino-4-(m-methoxyphenyD-A -1,3,- 4-thiadiazoline-2sulfonamide, etc.

The process by which the novel compounds of this res Patent 0 .diazolinei-Z-sulfonamide .is .used.

an C.

"2 invention may be preparedds illustrated schematically below using, 5-imino-4-methyl-A 1l ,SA-thiadiaz oline-Lsulfonarnide asan example of a suitable *5-imino-4-substitilted-A -1,3,4thiadiazolinee2-sulfonamide compound and phenylis'othiocyanate as an example of asuitable-isothiocyanate.

The invention will be described in greater detailin conjunction with the following specific examples in which the *parts are by weight 'unlessotherwise specified.

Example 1 Example. 2

The procedure of the preceding .:example is repeated with the exception that an equivalent quantityofmethyl- .isothiocyanate is used. '5-(NrmethylthiocarbamyD -imino-4-methyl-A -1,3,4-thiadiazolineeZrsuIfonamide is i pro- .duced.

Example 3 The procedure of Example .l-isjfollowed except that an equivalent. quantity of ,5imino 4rbenzyl-A -1,3,4-thia- 5-(Nr snylthio a bamyl) imino-4-benzyl-M-1,3,4 thiadiazoline 2 sulfonamide is obtained.

Example 4 Following the procedure of Example 1, a solution of 5-imino-4-phenyl-A -1,3,4thiadiazoline-2-sulfonamide hydrochloride and propylisothiocyanate in dimethylaniline are heated on the steam bath for 3 hours. S-(N-propylthiocarbamyl)imino-4-phenyl-A 1,3,4-thiadiazoline 2- sulfonamide is produced.

Example 5 Following the procedure of Example 1, a solution of 5- imino-4-(m-tolyl)-A 1,3,4-thiadiaZoline-2 sulfonamide hydrocholride and phenylisothiocyanate are refluxed in reagent pyridine for 3 hours. S-(N-phenylthiocarbamylimino-4-(m-tolyl)-A -l,3,4-thiadiazoline-2-sulfonamide is produced.

Example 6 The procedure of the preceding examples is repeated using equivalent quantities of 5-imino-4-(p-chlorophenyD- A -1,3,4thiadiazoline 2 sulfonamide and benzylisothiocyanate. S-(N-benzylthiocarbarnyl)-imino-4 (p-chlorophenyl)-A -1,3,4-thiadiazoline-Z-sulfonamide' is produced.

Example 7 The procedure of Example 1 is followed with the exception that an equivalent quantity of 5-imino-4-(pacetamidophenyl)-A -1,3,4-thiadiazoline 2 sulfonamide thiadiazoline-Z-sulfonamide.-,

is used in place of the -imino-4-methyl compound used in Example 1. acetamidophenyl)-A 1,3,4-thiadiazo1ine-2-su1fonamide is obtained.

Example 8 The procedure of Example '1 is followed with 'theexception that an equivalent quantity of 5-imino-4-(mmethoxyphenyl)-A=-1,3,4-thiadiazoline 2 sulfonamide is used in place of the 5-imino-4-methyl compound of Example 1 and an equivalent quantity of chlorophenylisothiocyanate is used instead of the phenylisothiocyanate used in Example 1. 5-(N-p-chlorophenylthiocarbamyl)- imino-4-( m-methoxyphenyl)eA -1,3,4-thiadiazoline-2 sulfonamide is obtained. g

The compounds of this invention are excellent natriuretic agents, that is agents which enhance the excretion of sodium in the urine without necessarily changing the normal volume of urine excreted. The compounds may be administered orally and have been found to be efiective in dosages of fromS mg. to 100 mg. per kilogram of body weight. p 7

We claim: 1. S-thiocarbamylimino-4-substituted-A -1,3,4-thiadiaz oline-Z-sulfonamides of the formula:-

R-NN

wherein R is a member selected from the group of lower alkyl, phenyl, halo-substituted phenyl, nitro-substituted ,phenyl, amide-substituted phenyl, lower alkoxy-substituted phenyl, lower alkyl-substituted phenyl, and phenyllower-alkyl radicals. I i

2. S-(N-phenylthiocarbamyl)-imino-4-methyl-A -1,3,4-

- thiadiazoline-Z-sulfonamide.

3'. S-(N-methylthiocarbahiyl)-imino-4 methyl-A -1,3,4- thiadiazbline-Z-sulfonamide.

4. S-(N-phenylthiocarbamyl)-imino-4-benzyl-A -1,3,4- t hiadiazoline-2-sulfonamide. V

5. S-(N-propylthiocarbamyl) imino-4-pheny1-A 1,3,4-

6. 5 -(N-phenylthiocarbamyl)-imino --4- (m-tolyl) A- 1,3,4-thiadiazoline-Z-sulfonamide.

7. The method of preparing s thiocarbamyliminolisubstituted-o -l'fiA-thiadiazoline 2 sulfonamides of the formulaz' i wherein R is a member selected from thegroup consisting of lower alkyl, phenyl," halo-substituted phenyl, nitro substituted phenyl, amide-substituted phenyl,. lowerv alkoxy-substituted Qphenyl, lower alkyl-su bstituted phenyl,

which comprises reacting 5-imino-4-methyl-A -l,3,4-thiadiazoline-Z-sulfonamidewith phenylisothiocyanate in the presence of a basic organic solvent.

9. The method-of preparing 5-(methylthiocarbamyl)- imino-4-methyl-A -1,3,4-thiadiazoline 2 sulfonamide which comprises reacting 5-imino-4-methyl-A2-1,3,4-thiadiazoline 2-sulfonamide with methylisothiocyanate inthe presenceoif-a basiciorganicsolvent.. a p

10. Themethod of preparing 5-.(N-phenylthiocarbamyl)-imino-4-benzylA -.1,3, l-thiadiazo1ine --2 sulfona: mide which comprises reacting 5-imino-4-benzyl-A'L1,3,4 thiadiazoline 2-sulf onamide" with phefiylisothiocyanat in the presence of a bas ic organic solvent; 5 w i 11. Th e methotl of preparing 5.-(Nepropylthi ocanv bamyl)imino-4-pheny1 A -1,3,4 thiadiazoline 2 -s'u1fon'amide which comprises reacting 5-imino-4-phenyl-A2-1,3,4: thiadiazoline -Z-sulfonamide with propylisothiocyanatein the presence of abasic organic solvent. i 12. The method of preparing S-(N-phenylthiokzarbamyl) -imino-4-(m-tolyl) A -1;3 ,4-thiadiazoline-2-sulfonamide which comprisesreac ting 5 iminol-(m-tolyD1-A 1,3,4-thiadiazoline-2-sulfonamide with 'phenylisothiocyanate in the presence ofa basic organic so1vent..

Noreferences cited. l 

1. 5-THIOCARBAMYLIMINO-4-SUBSTITUTED-$2-1,3,4-THIADIAZOLINE-2-SULFONAMIDES OF THE FORMULA: 